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Abstract:

BACKGROUND?Cleft lip with or without cleft palate (CLP) and cleft palate only (CPO) have an
inherited component and, many studies suggest, a relationship with folate. Attempts to find folaterelated
genes associated with clefts have, however, often been inconclusive. This study examined
four SNPs related to folate metabolism (MTHFR 677 C?T, MTHFR 1298 A?C, MTHFD1 1958
G?A, and TC II 776 C?G) in a large Irish population to clarify their relationship with clefts.
METHODS?Cases and their parents were recruited from major surgical centers performing cleft
repairs in Ireland and a support organization. Data on risk factors, medical history, and DNA were
collected. Controls were pregnant women from the greater Dublin area (n = 1,599).
RESULTS?CLP cases numbered 536 and CPO cases 426 after exclusions. CPO mothers were
significantly more likely than controls to be MTHFR 677 TT, OR 1.50 (95% CI: 1.05?2.16; p = .03).
Log-linear analysis showed a borderline association (p = .07). Isolated CPO case mothers were
significantly more likely than controls to be homozygous for the MTHFD1 1958 G?A variant, OR
1.50 (95%CI: 1.08?2.09; p = .02). When multiple cases were added, both CPO cases and case mothers
were significantly more likely to be AA (p = .02 and p = .007, respectively). The CLP case-control
and mother-control analyses also showed significant effects, ORs 1.38 (95% CI: 1.05?1.82; p = .03)
and 1.39 (95% CI: 1.04?1.85; p = .03), respectively.
CONCLUSIONS?Associations were found for both CPO and CLP and MTHFD1 1958 G?A in
cases and case mothers. MTHFR 677 C?T could be a maternal risk factor for clefts but the
association was not strong. Because multiple comparisons were made, these findings require
additional investigation. Given the known association between MTHFD1 1958 G?A and NTDs,
these findings should be explored in more detail.

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